US9556159B2 - Renin inhibitor - Google Patents

Renin inhibitor Download PDF

Info

Publication number
US9556159B2
US9556159B2 US14/427,828 US201314427828A US9556159B2 US 9556159 B2 US9556159 B2 US 9556159B2 US 201314427828 A US201314427828 A US 201314427828A US 9556159 B2 US9556159 B2 US 9556159B2
Authority
US
United States
Prior art keywords
optionally substituted
alkoxy
halogen
alkyl
apci
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US14/427,828
Other languages
English (en)
Other versions
US20150232459A1 (en
Inventor
Toru Iijima
Yoichi Takahashi
Miki Hirai
Hiroshi Sugama
Yuko Togashi
Jingkang Shen
Guangxin Xia
Huixin WAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Pharmaceuticals Holding Co Ltd
Original Assignee
Shanghai Pharmaceuticals Holding Co Ltd
Mitsubishi Tanabe Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Pharmaceuticals Holding Co Ltd, Mitsubishi Tanabe Pharma Corp filed Critical Shanghai Pharmaceuticals Holding Co Ltd
Assigned to MITSUBISHI TANABE PHARMA CORPORATION, SHANGHAI PHARMACEUTICALS HOLDING CO., LTD. reassignment MITSUBISHI TANABE PHARMA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SHEN, JINGKANG, WAN, Huixin, XIA, GUANGXIN, TAKAHASHI, YOICHI, SUGAMA, HIROSHI, HIRAI, MIKI, IIJIMA, TORU, TOGASHI, Yuko
Publication of US20150232459A1 publication Critical patent/US20150232459A1/en
Application granted granted Critical
Publication of US9556159B2 publication Critical patent/US9556159B2/en
Assigned to SHANGHAI PHARMACEUTICALS HOLDING CO., LTD. reassignment SHANGHAI PHARMACEUTICALS HOLDING CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MITSUBISHI TANABE PHARMA CORPORATION
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to novel compounds which are useful as a medicine, especially as a renin inhibitor, or pharmaceutically acceptable salts thereof and to use, a process for preparation or intermediates thereof.
  • Renin inhibitors are expected as a medicine for the prevention and/or treatment of diseases such as hypertension, heart failure, diabetic nephropathy and the like, and 3,4-substituted piperidine derivatives are disclosed for example (Patent Literature 1). But a morpholine derivative is not described in the literature.
  • WO 2008/153182 discloses some morpholine derivatives but they are compounds having a formula I of the present invention wherein R is a hydrogen atom (Patent Literature 2).
  • Patent Literature 1 WO006/069788WO (US 2009/0312304A)
  • Patent Literature 2 WO2008/153182WO (US 2010/0240644A)
  • the present invention provides novel compounds having an excellent activity to inhibit renin.
  • the present invention is as follows;
  • R 1 is a cycloalkyl or an alkyl
  • an alkyl optionally substituted with same or different 1 or 2 groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyl, an aryl optionally substituted with a halogen, an alkoxy, or a haloalkoxy, a hydroxyl, an heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyl,
  • a heteroaryl optionally substituted with same or different 1 or 2 groups selected from an alkyl, an amino, a halogen and an alkoxy,
  • an alkyl optionally substituted with same or different 1 or 2 groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyl, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, an heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyl,
  • an alkyl optionally substituted with same or different 1 or 2 groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyl, an aryl optionally substituted with a halogen, an alkoxy, or a haloalkoxy, a hydroxyl, an heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyl,
  • an alkyl optionally substituted with same or different 1 or 2 groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyl, an aryl optionally substituted with a halogen, an alkoxy, or a haloalkoxy, a hydroxyl, an heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyl,
  • a heteroaryl optionally substituted with same or different 1 or 2 groups selected from an alkyl, an amino, a halogen and an alkoxy,
  • an alkenyl optionally substituted with same or different 1 or 2 groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyl, an aryl, a hydroxyl and a halogen, and
  • an alkyl optionally substituted with same or different 1 or 2 groups selected from an aryl, an alkoxy, a halogen atom and a hydroxyl,
  • an alkyl optionally substituted with same or different 1 or 2 groups selected from an alkanoylamino optionally substituted with a halogen, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyl, an aryl optionally substituted with a halogen, an alkoxy or a haloalkoxy, a hydroxyl, an heteroaryl, a halogen and an amino optionally substituted with 1 or 2 alkyl,
  • a Ring A is a pyrrolyl, an imidazolyl, a pyrazolyl, a thienyl, a thiazolyl, or a triazolyl,
  • heteroaryl optionally substituted with same or different 1 or 2 groups selected from an alkyl, and alkoxy (preferably said heteroaryl is a pyridyl, a pyrimidyl, or a pyrazolyl),
  • an aliphatic hetelocyclic ring (preferably said aliphatic hetelocyclic ring is a tetrahydropyranyl),
  • R 22 is selected from 2) the optionally substituted pyridyl, 3) the optionally substituted pyrazolopyridyl, 4) the optionally substituted indolyl, 10) the optionally substituted pyrrolopyridinyl, 23) the optionally substituted pyrazolyl, 25) the optionally substituted thiazolyl, 26) the optionally substituted triazolyl, 27) the optionally substituted pyrimidinyl, 28) the optionally substituted pyrazyl, or 29) the optionally substituted imidazopyridinyl, or a pharmaceutically acceptable salt thereof.
  • alkyl or “alkoxy” in the present invention is exemplified by a straight or branched chain group having 1 to 10 carbon atoms, and groups having 1 to 6 carbon atoms are preferable, and groups having 1 to 4 carbon atoms are especially preferable.
  • alkenyl is exemplified by a straight or branched chain group having 2 to 10 carbon atoms, and the group having 3 to 7 carbon atoms is preferable, and the group having 3 to 5 carbon atoms is especially preferable.
  • alkynyl is exemplified by a straight or branched chain group having 2 to 10 carbon atoms, and the group having 3 to 7 carbon atoms is preferable, and the group having 3 to 5 carbon atoms is especially preferable.
  • alkanoyl is exemplified by a straight or branched chain group having 1 to 7 carbon atoms, and the group having 2 to 5 carbon atoms is preferable.
  • cycloalkyl is exemplified by a cycloalkyl group having 3 to 8 carbon atoms, groups having 3 to 6 carbon atoms are preferable and groups having 3 to 4 carbon atoms are especially preferable.
  • halogen is exemplified by a fluorine, a chlorine, a bromine and an iodine, and a fluorine, a chlorine and a bromine are preferable, and a fluorine is especially preferable.
  • aryl is exemplified by a phenyl, a naphthyl and the like and a phenyl is preferable.
  • heteroaryl is, for example, an aromatic cyclic group comprising 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, including a monocyclic group having of 5- to 6-membered ring, a bicyclic group of 8- to 10-membered ring wherein same or different monocyclic heteroaromatic rings are fused to each other, and, a bicyclic group of 8- to 10-membered ring wherein a monocyclic heteroaromatic ring is fused to a benzene.
  • aliphatic heterocyclic ring in “aliphatic heterocyclic group” and “aliphatic heterocyclic oxy” is exemplified by, for example, a non-aromatic heterocyclic ring comprising 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms which have 5 to 12 ring members as a whole and which may be partially or fully saturated.
  • the lower alkyl in R is exemplified by, for example, a straight or branched chain group having 1 to 4 carbon atoms, and a methyl is especially preferable.
  • the cycloalkyl of R 1 the cyclopropyl is preferable.
  • one of said 1 to 3 substituents is preferably selected from
  • one of said 1 to 3 substituents is preferably
  • a (C2-4) alkyl optionally substituted with same or different 1 or 2 groups selected from an alkanoylamino, an alkoxycarbonylamino, an alkoxy, an aminocarbonylamino optionally substituted with 1 or 2 alkyl, aryl, hydroxyl, and a halogen, specifically, one of said 1 to 3 substituents is an alkoxycarbonylamino (C2-4)alkyl.
  • the “indolinyl” in 12) the optionally substituted indolinyl as R 22 includes an oxoindolinyl.
  • the compound [I] of the present invention can be clinically used either in the free form or in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the compound [I] include a salt with an inorganic acid such as hydrochloride, sulfate, phosphate or hydrobromide, or a salt with an organic acid such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate.
  • examples of the pharmaceutically acceptable salt include, salts with a base (such as alkaline metal such as sodium salt and potassium salt or alkaline earth metal such as calcium salt).
  • the compounds disclosed in Examples comprise a free form of any compounds discloses as a salt form in Examples.
  • the compound [I] of the present invention also includes a mixture of a stereoisomer such as a geometrical isomer, a tautomer and an enantiomer, and an isolated stereoisomer thereof.
  • a stereoisomer such as a geometrical isomer, a tautomer and an enantiomer, and an isolated stereoisomer thereof.
  • (R)-configuration is preferable for an asymmetric carbon atom of the morpholine ring having the substituent, R 6 , from the view of renin-inhibition. From the view of renin-inhibition, (R)-configuration is also preferable for an asymmetric carbon atom which is substituted with R.
  • the present invention also includes an intramolecular salt, a hydrate, a pharmaceutically acceptable solvate and a crystal polymorph of the compound [I]. Additionally it should be understood that the compound [I] of the present invention is not limited to the compounds described in the examples below but includes whole the compounds of the formula [I] and pharmaceutically acceptable salts thereof.
  • the compound of the present invention or the pharmaceutically acceptable salts thereof may be useful as an agent for prevention and/or treatment of hypertension, cardiac failure, diabetic nephropathy and the like, and can be advantageous as a medicine due to its low toxicity.
  • the compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be either orally or parenterally administered, and can be formulated into a conventional pharmaceutical preparation such as tablets, granules, capsules, powders, injections or inhalants etc.
  • the dose of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof may vary in accordance with the administration routes, and the ages, body weights and conditions of the patients, but usually it is in the range of about 0.001 to 500 mg/kg, preferably in the range of about 0.1 to 100 mg/kg.
  • the compound [I] of the present invention can be prepared by the following methods but should not be construed to be limited thereto.
  • the compound [I] of the present invention or the pharmaceutically acceptable salt thereof can be prepared by deprotecting P 1 of the compound of the formula [II];
  • the compound [II] can be prepared by reacting a carboxylic compound of the formula [III]:
  • the compound of the present invention has two or more asymmetric carbons and the reaction product may be obtained as a mixture of diastereoisomers.
  • a mixture of diastereoisomers can be separated and purified by a usual method, a silica gel column chromatography for example.
  • Examples of the protecting group shown as P 1 include a usual amino-protecting group such as a t-butoxycarbonyl, a benzyloxycarbonyl, a 4-methoxybenzyloxycarbonyl, a benzyl, a 4-methoxybenzyl, an acetyl, a benzoyl, a tosyl and the like.
  • the protecting group P 1 of the compound [II] can be deprotected by treating with acid or base or catalytic reduction or a deprotecting agent in a suitable solvent or without solvent.
  • acid an inorganic acid such as hydrochloric acid, sulfuric acid and the like, and an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like can be preferably used.
  • an inorganic base e.g., an alkali metal hydride such as sodium hydride, an alkali metal carbonate such as sodium carbonates and potassium carbonates, an alkali metal amide such as sodium amides and lithium amide, an alkali metal alkoxide such as sodium methoxide, an alkali metal such as sodium, and an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide etc.
  • an alkali metal hydride such as sodium hydride
  • an alkali metal carbonate such as sodium carbonates and potassium carbonates
  • an alkali metal amide such as sodium amides and lithium amide
  • an alkali metal alkoxide such as sodium methoxide
  • an alkali metal such as sodium
  • an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide etc.
  • zinc bromide and trimethylsilane trifluoromethanesulfonate etc. can be used.
  • the catalytic reduction can be carried out by preferably using palladium carbon, palladium hydroxide carbon, platinum oxide and the like as a catalyst under hydrogen atmosphere.
  • the solvent include any solvent which does not disturb the reaction, such as methanol, ethanol, isopropyl alcohol, 1,4-dioxane, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, ethyl acetate, toluene, and a mixture thereof.
  • the acid or the base described above can be used as the solvent.
  • the reaction can be suitably carried out at from ⁇ 78° C. to a boiling temperature of the solvent.
  • the compound [II] can be prepared by a condensation reaction of a carboxylic acid compound [III] and an amine compound [IV] in a suitable solvent or without a solvent.
  • the condensation reaction can be carried out by a conventional condensation reaction in the presence of a condensing agent, or reacting an activated derivative of the compound [III](e.g., an acid halide, a mixed acid anhydride, an activated ester and the like) with the compound [IV], after the compound [III] is converted to the reactive derivative thereof.
  • a condensing agent e.g., an acid halide, a mixed acid anhydride, an activated ester and the like
  • condensing agent examples include N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or hydrochloride thereof, carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethyl cyanophosphonate (DEPC) and the like, and among them DCC. EDC or its hydrochloride is preferable.
  • the reactive derivative of the compound [III] can be reacted with the compound [IV] in a suitable solvent or without a solvent in presence of an acid scavenger if necessary, after the compound [III] is converted to an acid halide using a halogenating agent (e.g., thionyl chloride, thionyl bromide, oxalyl chloride and the like), a mixed acid anhydride using chlorocarbonate ester (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chloroformate and the like) or acid chloride (2,4,6-trichlorobenzoyl chloride and the like), or an activated ester of N-hydroxylamine compound (1-hydroxysuccinimide, 1-hydroxybenzotriazole and the like) or of phenol compound (p-nitrophenol and the like) or a lower alcohol ester (methyl ester, ethyl ester and the like).
  • a halogenating agent
  • an addition of catalyst such as dimethylformamide and the like can accelerate the reaction.
  • an acid scavenger an inorganic base or an organic base is used when necessary, and examples of an inorganic base include sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like and examples of an organic base include triethylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undeca-7-ene, N,N-diethylaniline, pyridine, lutidine, colidine and the like.
  • triethylamine, diisopropylethylamine, pyridine and the like are preferably used as an acid scavenger.
  • acid scavenger is used as the solvent.
  • any inert solvent which does not disturb the reaction can be used and examples of the solvents include chloroform, dichloromethane, dichloroethane, toluene, diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ethyl acetate, amide-related solvent (N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinon etc.), pyridine, 2,6-lutidine, water and the like, and a mixture thereof can be also used.
  • chloroform tetrahydrofuran, dioxane, N,N-dimethylformamide. N,N-dimethylacetamide, and a mixture of chloroform and N,N-dimethylformamide etc. are preferred.
  • condensation reaction above can be carried out at a temperature from ⁇ 20° C. to a reflux temperature of the solvent and if necessary, it can be carried out at a lower temperature which is suitably selected.
  • Example No. Chemical Formula MS Result MS Method Ion Species Example 7 414 APCI [M + H]+ Example 8 414 APCI [M + H]+ Example 9 430 APCI [M + H]+ Example 10 391 APCI [M + H]+ Example 11 426 APCI [M + H]+ Example 12 401 APCI [M + H]+ Example 13 403 APCI [M + H]+
  • Example 14 405 APCI [M + H]+ Example 15 401 APCI [M + H]+ Example 16 419 APCI [M + H]+ Example 17 414 APCI [M + H]+ Example 18 421/423 APCI [M + H]+ Example 19 419 APCI [M + H]+ Example 20 415 APCI [M + H]+
  • Example 21 416 APCI [M + H]+ Example 22 402 APCI [M + H]+ Example 23 405 APCI [M + H]+ Example 24 417 APCI [M + H]+ Example 25 392 APCI [M + H]+ Example 26 401 APCI [M + H]+ Example 27 404 APCI [M + H]+
  • Example 28 443 APCI [M + H]+ Example 29 444 APCI [M + H]+ Example 30 415 APCI [M + H]+ Example 31 401 APCI [M + H]+ Example 32 414 APCI [M + H]+ Example 33 401 APCI [M + H]+
  • Example 34 401 APCI [M + H]+ Example 35 429 APCI [M + H]+ Example 36 441 APCI [M + H]+ Example 37 429 APCI [M + H]+ Example 38 429 APCI [M + H]+ Example 39 401 APCI [M + H]+
  • Example 40 431 APCI [M + H]+ Example 41 460 APCI [M + H]+ Example 42 444 APCI [M + H]+ Example 43 430 APCI [M + H]+ Example 44 402 APCI [M + H]+ Example 45 430 APCI [M + H]+
  • Example 46 416 APCI [M + H]+ Example 47 401 APCI [M + H]+ Example 48 400 APCI [M + H]+ Example 49 414 APCI [M + H]+ Example 50 414 APCI [M + H]+ Example 51 431 APCI [M + H]+
  • Example 52 431 APCI [M + H]+ Example 53 415 APCI [M + H]+ Example 54 415 APCI [M + H]+ Example 55 445 APCI [M + H]+ Example 56 415 APCI [M + H]+ Example 57 431 APCI [M + H]+
  • Example 58 459 APCI [M + H]+ Example 59 470 APCI [M + H]+ Example 60 422 APCI [M + H]+ Example 61 390 APCI [M + H]+ Example 62 444 APCI [M + H]+ Example 63 460 APCI [M + H]+
  • Example 64 431 APCI [M + H]+ Example 65 460 APCI [M + H]+ Example 66 460 APCI [M + H]+ Example 67 458 APCI [M + H]+ Example 68 418 APCI [M + H]+ Example 69 416 APCI [M + H]+
  • Example 70 445 APCI [M + H]+ Example 71 427 APCI [M + H]+ Example 72 499 APCI [M + H]+ Example 73 430 APCI [M + H]+ Example 74 421 APCI [M + H]+ Example 75 448 APCI [M + H]+
  • Example 76 448 APCI [M + H]+ Example 77 419 APCI [M + H]+ Example 78 392 APCI [M + H]+ Example 79 429 APCI [M + H]+ Example 80 402 APCI [M + H]+ Example 81 474 APCI [M + H]+
  • Example 82 471 APCI [M + H]+ Example 83 502 APCI [M + H]+ Example 84 431 APCI [M + H]+ Example 85 420 APCI [M + H]+ Example 86 459 APCI [M + H]+
  • Example 92 408 APCI [M + H]+
  • Example 93 416 APCI [M + H]+
  • Example 94 459 APCI [M + H]+
  • Example 95 436 APCI [M + H]+
  • Example 96 434 APCI [M + H]+
  • Example 97 405 APCI [M + H]+
  • Example 98 425/427 APCI [M + H]+
  • Example 99 433 APCI [M + H]+
  • Example 100 488 APCI [M + H]+
  • Example 101 445 APCI [M + H]+
  • Example 102 445 APCI [M + H]+
  • Example 103 416 APCI [M + H]+
  • Example 104 447 APCI [M + H]+
  • Example 105 475 APCI [M + H]+
  • Example 106 434 APCI [M + H]+
  • Example 112 390 APCI [M + H]+
  • Example 113 415 APCI [M + H]+
  • Example 114 508/510 APCI [M + H]+
  • Example 115 445 APCI [M + H]+
  • Example 116 415 APCI [M + H]+
  • Example 137 459 APCI [M + H]+
  • Example 138 444 APCI [M + H]+
  • Example 139 448 APCI [M + H]+
  • Example 140 429 APCI [M + H]+
  • Example 141 471 APCI [M + H]+
  • Example 142 459 APCI [M + H]+
  • Example 148 419 APCI [M + H]+ Example 149 441 APCI [M + H]+ Example 150 440 APCI [M + H]+ Example 151 445 APCI [M + H]+ Example 152 443 APCI [M + H]+ Example 153 473 APCI [M + H]+
  • Example 159 456 APCI [M + H]+
  • Example 160 427 APCI [M + H]+
  • Example 161 440 APCI [M + H]+
  • Example 162 473 APCI [M + H]+
  • Example 163 470 APCI [M + H]+
  • Example 164 524 APCI [M + H]+
  • Example 165 474 APCI [M + H]+
  • Example 166 473 APCI [M + H]+
  • Example 167 431 APCI [M + H]+
  • Example 168 474 APCI [M + H]+
  • Example 179 470 APCI [M + H]+
  • Example 180 471 APCI [M + H]+
  • Example 181 422 APCI [M + H]+
  • Example 182 456 APCI [M + H]+
  • Example 183 456 APCI [M + H]+
  • Example 189 434 APCI [M + H]+
  • Example 190 420 APCI [M + H]+
  • Example 191 436 APCI [M + H]+
  • Example 192 474 APCI [M + H]+
  • Example 193 474 APCI [M + H]+
  • Example 194 431 APCI [M + H]+ Example 195 461 APCI [M + H]+ Example 196 459 APCI [M + H]+ Example 197 472 APCI [M + H]+ Example 198 474 APCI [M + H]+ Example 199 474 APCI [M + H]+
  • Example 200 411 APCI [M + H]+ Example 201 400 APCI [M + H]+ Example 202 470 APCI [M + H]+ Example 203 524 APCI [M + H]+ Example 204 461 APCI [M + H]+ Example 205 428 APCI [M + H]+
  • Example 206 473 APCI [M + H]+ Example 207 515 APCI [M + H]+ Example 208 458 APCI [M + H]+ Example 209 408 APCI [M + H]+ Example 210 462 APCI [M + H]+
  • Example 222 470 APCI [M + H]+ Example 223 489 APCI [M + H]+ Example 224 396 APCI [M + H]+ Example 225 422 APCI [M + H]+ Example 226 487 APCI [M + H]+
  • Example 232 427 APCI [M + H]+
  • Example 233 448 APCI [M + H]+
  • Example 234 489 APCI [M + H]+
  • Example 235 491 APCI [M + H]+
  • Example 236 487 APCI [M + H]+
  • Example 237 435 APCI [M + H]+
  • Example 238 435 APCI [M + H]+
  • Example 239 513 APCI [M + H]+
  • Example 240 476 APCI [M + H]+
  • Example 241 476 APCI [M + H]+
  • Example 242 474 APCI [M + H]+ Example 243 486 APCI [M + H]+ Example 244 474 APCI [M + H]+ Example 245 436 APCI [M + H]+ Example 246 464 APCI [M + H]+
  • Example 252 498 APCI [M + H]+
  • Example 253 578 APCI [M + H]+
  • Example 254 503 APCI [M + H]+
  • Example 255 475 APCI [M + H]+
  • Example 256 516 APCI [M + H]+
  • Example 272 478 ESI [M + H]+ Example 273 503 APCI [M + H]+ Example 274 506 APCI [M + H]+ Example 275 524 APCI [M + H]+ Example 276 556 ESI [M + H]+
  • Example 304 436 APCI [M + H]+ Example 305 509 APCI [M + H]+ Example 306 485 APCI [M + H]+ Example 307 509 APCI [M + H]+ Example 308 451 ESI [M + H]+
  • Example 309 465 ESI [M + H]+
  • Example 310 465 ESI [M + H]+
  • Example 311 479 APCI [M + H]+
  • Example 312 503 APCI [M + H]+
  • Example 313 472 APCI [M + H]+
  • Example 334 570 APCI [M + H]+ Example 335 476 APCI [M + H]+ Example 336 482 APCI [M + H]+ Example 337 515 APCI [M + H]+ Example 338 515 APCI [M + H]+
  • Example 429 238.5 [M + 2H] 2+
  • Example 430 237.0 [M + 2H] 2+
  • Example 431 245.0 [M + 2H] 2+
  • Example 432 245.0 [M + 2H] 2+
  • a starting material [REx(19-1)] is prepared from, for example, 1-bromo-3-fluoro-phenol according to the conventional manner (such as the method of Reference Example 7 (3)).
  • a starting compound [REx(23-1)] is obtained by 3-methoxypropylation at N of 6-bromo-1-1H-pyrrolo[3,2-b]pyridine.
  • the compound obtained in the above (1) (1.69 g) was dissolved in chloroform (20 mL), and then thereto was added 4-normal hydrogen chloride/1,4-dioxane under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. Then, thereto was added aqueous saturated sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure.
  • the resulting residue was dissolved in acetonitrile (20 mL), and then thereto were added sodium hydroxide (320 mg) and tetrabutylammonium hydrogen sulfate (68 mg), and the mixture was stirred at 50° C. for 30 minutes.
  • the reaction solution was cooled, and then an insoluble was filtered, and the filtrate was concentrated under reduced pressure.
  • the resulting residue was dissolved in ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure.
  • reaction solution was poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated saline, and then dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure.
  • a substrate of synthetic peptide (Nma-KHPFH LVIHK(Dnp)-NH 2 ) and test compound were mixed, and fluorescence intensity was assayed using a fluorophotometer before starting an enzymatic reaction (exciting wavelength: 340 nm, measuring wavelength: 460 nm).
  • Recombinant human renin was added and the mixture was incubated at 37° C. for 1 hour, and the fluorescence intensity was measured after the reaction using a fluorophotometer (exciting wavelength: 340 nm, measuring wavelength: 460 nm).
  • Renin activity was evaluated on the ground of fluorescence intensity which was obtained by deduction of the intensity before the reaction from the intensity after the reaction, and 50%/a inhibitory concentration (IC 50 ) was calculated from renin activities under the existence of various concentration of the test compound.
  • Example compounds herein showed the following values.
  • the compound [I] of the present invention or a pharmaceutically acceptable salt thereof has renin inhibitory activity and may be useful for treatment and/or prophylaxis of hypertension, cardiac failure, diabetic nephropathy and the like. Furthermore, the compound [II] is useful as a synthetic intermediate for preparing the compound [I].

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
US14/427,828 2012-09-14 2013-09-13 Renin inhibitor Active US9556159B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2012-203471 2012-09-14
JP2012203471 2012-09-14
PCT/JP2013/074941 WO2014042263A1 (ja) 2012-09-14 2013-09-13 新規レニン阻害薬

Publications (2)

Publication Number Publication Date
US20150232459A1 US20150232459A1 (en) 2015-08-20
US9556159B2 true US9556159B2 (en) 2017-01-31

Family

ID=50278368

Family Applications (1)

Application Number Title Priority Date Filing Date
US14/427,828 Active US9556159B2 (en) 2012-09-14 2013-09-13 Renin inhibitor

Country Status (7)

Country Link
US (1) US9556159B2 (zh)
EP (1) EP2933248B1 (zh)
JP (1) JP6158193B2 (zh)
CN (1) CN104640847B (zh)
ES (1) ES2662026T3 (zh)
TW (1) TWI606041B (zh)
WO (1) WO2014042263A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160145220A1 (en) * 2011-03-16 2016-05-26 Mitsubishi Tanabe Pharma Corporation Nitrogen-containing saturated heterocyclic compound

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5764628B2 (ja) * 2012-09-14 2015-08-19 田辺三菱製薬株式会社 医薬組成物
EP3398946B1 (en) * 2015-12-29 2022-05-04 Shanghai Pharmaceuticals Holding Co., Ltd. Salt of morpholine derivative and crystalline form thereof, as well as preparation method, pharmaceutical composition and use of the same
EP3538520A2 (en) 2016-11-08 2019-09-18 Cyclerion Therapeutics, Inc. Sgc stimulators
CN109232251B (zh) * 2018-09-05 2022-03-25 潍坊医学院 青心酮衍生物、其制备方法、应用及药物组合物
CN111423411B (zh) * 2020-04-02 2021-04-16 南京生命源医药科技有限公司 一种新型肾素抑制剂
EP4242195A1 (en) * 2022-03-09 2023-09-13 EuroChem Antwerpen Use of pyrazolo[3,4-b]pyridine compounds as nitrification inhibitor
WO2024093907A1 (zh) * 2022-10-31 2024-05-10 大睿生物医药科技(上海)有限公司 向眼部和中枢神经系统递送sirna的配体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008515916A (ja) 2004-10-07 2008-05-15 ビテ ファーマシューティカルズ， インコーポレイテッド ジアミノアルカンアスパラギン酸プロテアーゼ阻害剤
JP2008526701A (ja) 2004-12-30 2008-07-24 ノバルティス アクチエンゲゼルシャフト 有機化合物
WO2008153182A1 (ja) 2007-06-15 2008-12-18 Mitsubishi Tanabe Pharma Corporation モルホリン誘導体
WO2012124775A1 (ja) 2011-03-16 2012-09-20 田辺三菱製薬株式会社 含窒素飽和複素環化合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0500784D0 (en) * 2005-01-14 2005-02-23 Novartis Ag Organic compounds
JP2010064982A (ja) * 2008-09-10 2010-03-25 Dainippon Sumitomo Pharma Co Ltd アルキルアミノ誘導体
JP2012149054A (ja) * 2010-12-27 2012-08-09 Dainippon Sumitomo Pharma Co Ltd Ｎ−置換−環状アミノ誘導体からなる医薬
JP5764628B2 (ja) * 2012-09-14 2015-08-19 田辺三菱製薬株式会社 医薬組成物

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008515916A (ja) 2004-10-07 2008-05-15 ビテ ファーマシューティカルズ， インコーポレイテッド ジアミノアルカンアスパラギン酸プロテアーゼ阻害剤
US20090018103A1 (en) 2004-10-07 2009-01-15 Vitae Pharmaceutical, Inc Diaminoalkane Aspartic Protease Inhibitors
JP2008526701A (ja) 2004-12-30 2008-07-24 ノバルティス アクチエンゲゼルシャフト 有機化合物
US20090312304A1 (en) 2004-12-30 2009-12-17 Werner Breitenstein Organic compounds
WO2008153182A1 (ja) 2007-06-15 2008-12-18 Mitsubishi Tanabe Pharma Corporation モルホリン誘導体
EP2168952A1 (en) 2007-06-15 2010-03-31 Mitsubishi Tanabe Pharma Corporation Morpholine derivative
US20100240644A1 (en) 2007-06-15 2010-09-23 Hidenori Akatsuka Morpholine derivative
WO2012124775A1 (ja) 2011-03-16 2012-09-20 田辺三菱製薬株式会社 含窒素飽和複素環化合物
CA2828378A1 (en) 2011-03-16 2012-09-20 Mitsubishi Tanabe Pharma Corporation Nitrogen-containing saturated heterocyclic compound
EP2687518A1 (en) 2011-03-16 2014-01-22 Mitsubishi Tanabe Pharma Corporation Nitrogen-containing saturated heterocyclic compound

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
English translation of the International Preliminary Report on Patentability and Written Opinion issued Mar. 26, 2015, in PCT International Application No. PCT/JP2013/074941.
Extended European Search Report for Application No. 13836321.3 dated Mar. 14, 2016.
International Search Report, issued in PCT/JP2013/074941, dated Nov. 26, 2013.
STN on the Web, publication date of Apr. 19, 2011, File Registry, RN=1282600-96-7.
STN on the Web, publication date of Jun. 1, 2011, File Registry, RN=1304061-38-8, 1304060-57-8, 1304060-53-4.
STN on the Web, publication date of Jun. 2, 2011, File Registry, RN=1304196-50-6.
STN on the Web, publication date of Jun. 5, 2011, File Registry, RN=1305533-03-2.
STN on the Web, publication date of Jun. 8, 2011, File Registry, RN=1307879-67-9.
STN on the Web, publication date of Jun. 9, 2011, File Registry, RN=1308143-41-0, 1308142-47-3.
STN on the Web, publication date of May 8, 2011, File Registry, RN=1291670-16-0, 1291669-94-7, 1291669-93-6, 1291669-90-3, 1291669-83-4, 1291669-80-1.
STN on the Web, publication date of May 9, 2011, File Registry, RN=1291958-82-1, 1291958-76-3, 1291897-95-4, 1291897-93-2.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160145220A1 (en) * 2011-03-16 2016-05-26 Mitsubishi Tanabe Pharma Corporation Nitrogen-containing saturated heterocyclic compound
US10155731B2 (en) * 2011-03-16 2018-12-18 Mitsubishi Tanabe Pharma Corporation Nitrogen-containing saturated heterocyclic compound

Also Published As

Publication number Publication date
CN104640847B (zh) 2019-10-15
EP2933248B1 (en) 2018-01-31
ES2662026T3 (es) 2018-04-05
CN104640847A (zh) 2015-05-20
TWI606041B (zh) 2017-11-21
JPWO2014042263A1 (ja) 2016-08-18
US20150232459A1 (en) 2015-08-20
TW201418233A (zh) 2014-05-16
WO2014042263A1 (ja) 2014-03-20
EP2933248A4 (en) 2016-04-13
JP6158193B2 (ja) 2017-07-05
EP2933248A1 (en) 2015-10-21

Similar Documents

Publication Publication Date Title
US9556159B2 (en) Renin inhibitor
US20230116233A1 (en) Compounds And Compositions As Protein Kinase Inhibitors
US11787813B2 (en) Substituted pyrazolopyrimidines and substituted purines and their use as ubiquitin-specific-processing protease 1 (USP1) inhibitors
US11845760B2 (en) PRMT5 inhibitors
US10358446B2 (en) Bruton's tyrosine kinase inhibitors
US9890168B2 (en) 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medicinal use thereof
US8729271B2 (en) Glycine transporter inhibiting substances
US10155731B2 (en) Nitrogen-containing saturated heterocyclic compound
JP2022507013A (ja) Ｈ４アンタゴニスト化合物としてのピラゾール誘導体
US20240116921A1 (en) Lactam (hetero)arylfusedpyrimidine derivatives as inhibitors of erbb2
WO2020187292A1 (zh) 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用
US20240228491A1 (en) Methionine adenosyltransferase inhibitor, preparation method therefor and application thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: MITSUBISHI TANABE PHARMA CORPORATION, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:IIJIMA, TORU;TAKAHASHI, YOICHI;HIRAI, MIKI;AND OTHERS;SIGNING DATES FROM 20141121 TO 20141226;REEL/FRAME:035160/0646

Owner name: SHANGHAI PHARMACEUTICALS HOLDING CO., LTD., CHINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:IIJIMA, TORU;TAKAHASHI, YOICHI;HIRAI, MIKI;AND OTHERS;SIGNING DATES FROM 20141121 TO 20141226;REEL/FRAME:035160/0646

STCF Information on status: patent grant

Free format text: PATENTED CASE

AS Assignment

Owner name: SHANGHAI PHARMACEUTICALS HOLDING CO., LTD., CHINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MITSUBISHI TANABE PHARMA CORPORATION;REEL/FRAME:048689/0399

Effective date: 20190215

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8